The home run reported this week was in a practice game in a minor league. But nonetheless the results are impressive and lead to hope for those suffering from certain forms of congenital blindness and vision impairment. The report leading to this optimism, Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose-escalation trial, appeared in the November 7 edition of The Lancet.
The trial involved 12 patients (aged 8—44 years), all having Leber’s congenital amaurosis (LCA), “a rare inherited eye disease that appears at birth or in the first few months of life, and affects around 1 in 80,000 of the population.”
People with this disease are born with impaired vision and their vision deteriorates until they are totally blind, usually within 10-15 years. “Typically a baby with LCA will have very reduced vision at birth although the retina may appear normal when first examined. Within months, however, parents will usually notice nystagmus – an involuntary, rhythmical, repeated movement of the eyes. Children with LCA account for 10-18% of all cases of congenital blindness. Vision in individuals with LCA varies greatly from relatively mild acuity problems (20/70) to no light perception(ref).” Up to this point, the disease has been incurable.
LCA is an autosomal recessive disorder, which means that if both parents are carriers of a defective gene as well as a good gene, there is a 1 in 4 chance the child will end up with two defective genes and manifest the disease. The 12 patients in the recent trial had a variant of LCA caused a defect in the RPE65 gene(ref)(ref), a gene responsible for encoding the retinal pigment epithelium-specific 65 kDa protein. This protein “is located in the retinal pigment epithelium and is involved in the conversion of all-trans retinol to 11-cis retinal during phototransduction, which is then used in visual pigment regeneration in photoreceptor cells(ref).”
The therapy used in “home run” trial is a simple one. Each of the 12 patients were given one given one subretinal injection using a thin needle in the worst eye of a “defanged” adeno-associated virus (AAV) into which the RPE65 gene had been inserted. “The engineered virus then invaded retinal cells and inserted the gene into the cells’ DNA. — Within two weeks, the treated eyes began to become more sensitive to light, and within a few more weeks, vision began to improve. The younger the patients were, the better they responded. — By both objective and subjective measures, vision improved for all the patients. They were able to navigate obstacle courses, read eye charts and perform most of the tasks of daily living. The children who were treated “are now able to walk and play just like any normally sighted child — The improvement has now persisted for as long as two years(ref).” There appeared to be no safety issues or adverse effects involved.
“The study “holds great promise for the future” and “is appealing because of its simplicity,” wrote researchers from the Nijmegen Medical Center in the Netherlands in an editorial accompanying the report –(ref).” The study had its limits of course. The patients would like to have their other eye treated and optimum dosage of the adenovirus/RPE65 is not yet determined. Yet the results lend hope to the other some 130,000 victims of LCA worldwide as well as to victims of other more common hereditary eye diseases such as Retinitis pigmentosa.
After many years of false starts and problematical trials, it appears that gene therapies may finally be getting off the ground. See also the recent post ALD and lentivirus vectors for gene therapy.